The etiology of cleft lip with or without cleft palate (CLP), a serious and common birth defect, is unknown. Recent studies using complex segregation and linkage analysis have suggested that CLP has a single gene etiology. A recent genetic epidemiologic study showed that 13% of families ascertained y a proband with CLP had CLP recurring in an autosomal dominant pattern. Our overall objective is to delineate the molecular etiology of CLP. The specific aim of this study is to use both genetic epidemiologic and molecular methods to determine whether a single gene locus has na etiologic role in CLP. This will be accomplished by 1) Complex segregation analysis of 82 CLP families to determine which model, single gene, multifactorial or mixed, best accounts for the heritability of CLP 2) Further pedigree characterization of eleven multigenerational families with CLP, most consistent with an autosomal dominant pattern of inheritance. 3) Selection of 3 of the eleven families for a DNA linkage study including collection of blood samples from family members, transformation of cell lines and preparation of their DNA. 4) DNA linkage analysis in these 3 families to confirm or exclude linkage of CLP to: factor 13a) on chromosome 6 and transforming growth factor alpha (TGFA) on chromosome 2. If linkage is confirmed flanking markers will be identified and linkage in other families will be tested. 5) If linkage is excluded, variable number tandem repeat (VNTR) probes will be used to search for a clefting locus in these families. The results of this study will provide a new set of molecular probes necessary for better diagnosis of CLP and will ultimately permit us to resolve the molecular mechanisms responsible for CLP.